Animal genetic models have been essential to the understanding and treatment of human retinal degenerative disease. The importance of the retinal pigment epithelium (RPE) to photoreceptor function is widely recognized. Primary degeneration of RPE cells is thought to be central to the etiology of several significant human retinal disorders including age-related macular degeneration (AMD) and pigmentary retinopathies associated with mitochondrial dysfunction, yet no animal genetic model of a primary RPE cell degeneration exists. This proposal describes a strategy to create such a model using mouse genetics. A mouse strain will be generated in which RPE cells gradually and postnatally degenerate and die due to RPE specific loss of mitochondrial function. RPE cell degeneration should induce secondary photoreceptor cell degeneration and choroidal atrophy. A detailed structural and functional analysis of the effects of RPE cell loss on the RPE and adjacent tissues will be performed at various ages. At an appropriate stage in the degeneration, the model will be perturbed by modulating light exposure. A model of primary RPE cell degeneration will be useful for understanding the interdependence of RPE and photoreceptor cells and of the RPE and choroid, for understanding pathogenic processes secondary to RPE cell death, and for investigating potential therapies in a setting in which RPE cell function is progressively compromised.